Proteolytic modification of the extracellular matrix is essential for tissue remodeling, but also for the progression of a number of diseases, including head and neck cancer. The overall aim of this project is to understand the biochemistry, biology, and pathology of selected matrix remodeling serine proteases. We are particularly interested in the plasminogen activation (PA) system, a complex system of serine proteases, protease inhibitors, and protease receptors, whose primary function is to govern the conversion of the abundant plasma protease zymogen, plasminogen (Plg), to the active, multifunctional protease, plasmin. Plasmin acts directly or indirectly, via activation of latent pro-collagenases, to degrade components of the extracellular matrix during cell migration and tissue remodeling in development, homeostasis, tissue repair, and reproduction. In addition to degrading extracellular matrix glycoproteins, the plasminogen activation system also takes part in several other physiological processes, such as cytokine processing, signal transduction, leukocyte activation, chemotaxis, and angiogenesis inhibition. Beside its pleiotropic functions in physiological tissue remodeling, the plasminogen activation system has been implicated in the pathogenesis of a remarkable array of important human degenerative diseases, most notably tumor dissemination, atherosclerosis, rheumatoid arthritis, and ischemic brain damage. The plasminogen activation system also plays a critical role in bacterial infection, and a variety of bacterial pathogens are equipped with their own plasminogen activators, or display high affinity cell-surface receptors for plasmin. The Proteases and Tissue Remodeling Unit (PTRU) was established in July 1999 as a new laboratory in the Oral and Pharyngeal Cancer Branch. A major part of the research of the PTRU is focused on understanding the biochemistry, biology, and pathology of the plasminogen activation system. Areas of particular interest to the PTRU include the identification of the target substrates for plasmin during physiological and pathological tissue remodeling,, the identification of physiological initiators of the plasminogen activation cascade, and the function of the plasminogen activator receptor. We are also initiating a program to identify genes that are induced during incisional skin wound healing and squamous cell carcinoma. The overall long-term purpose of this project is to identify and characterize novel proteases that serve critical functions in physiological and pathological degradation of the extracellular matrix during tissue remodeling. The studies of the PTRU are carried out in collaboration with a number of researchers within the intramural and extramural communities, both nationally and internationally.